Currently, research and development has been directed to the development of new drugs and therapeutic agents to battle a variety of illness and diseases. Frequently, the nature of these new drugs and therapeutic agents limit the method of delivery that may be used to deliver the agent (e.g., the skin, the oral mucosa, the gastrointestinal tract, the blood-brain barrier). Additionally, the rate of transport of the new drugs and therapeutic agents may be less than optimal or effective and are therapeutically ineffective. Therefore, it is necessary to develop alternative delivery techniques.
Drugs may be commonly administered in a variety of ways e.g., orally as liquids, pills or capsules, across a biological barrier as syringes, transdermal patch or catheters, however these methods of delivery each have limitations and disadvantages. Orally administered drugs or therapeutic agents may face degradation in the gastrointestinal tract and/or elimination by the liver and thus, limit the efficiency of the treatment. Additionally, some drugs or therapeutic agents cannot effectively diffuse across the intestinal mucosa rendering them ineffective. Often oral treatments require administering treatment at particular intervals over a prolonged time, which raise the issue of patient compliance.
Another common method of delivering drugs or therapeutic agents across a biological barrier is by using a needle (e.g., standard syringes or catheters) to transport drugs through the skin. The use of needles is inconvenient for the patient, and often painful, particularly when frequent samples are required, e.g., diabetic patients. The invasiveness of methods involving conventional needles results in pain; local damage to the skin at the site of insertion; bleeding that increases the risk of disease transmission; and a wound sufficiently large enough to be a site of infection. In some cases, needle treatments are too painful and inconvenient or impractical for continuous controlled drug delivery over a period of hours or days. Additionally, needle phobias may result that lead to a significant risk to the life and health from the avoidance of medical or dental care. Therefore, methods using conventional needles for drug delivery is undesirable for prolonged treatments due to vascular damage caused by repeated punctures (e.g., as a result of a diabetic's delivery of insulin). Furthermore, needle techniques often require administration by a person trained in its use.
In addition to administering agents across a biological barrier, needles may be often used to withdraw biological substances from one side of a biological barrier, e.g., bodily fluids, such as for diagnostic purposes or sampling of biological fluids (e.g., diabetic's blood glucose sampling). The invasiveness of withdrawing samples using conventional needles results in pain; local damage to the skin at the site of insertion; bleeding that increases the risk of disease transmission; and a wound sufficiently large enough to be a site of infection. Less painful methods for obtaining a sample are known, such as lancing the arm or thigh, which have a lower nerve ending density, however sampling of such areas often result in inadequate results as those locations are not heavily supplied with near-surface capillary vessels. Currently, no alternative methodologies are available to address these problems. Proposed alternatives to the conventional needle, require the use of lasers or heat to create a hole in the skin, which is inconvenient, expensive, and/or undesirable for repeated use.
Another delivery technique includes the use of a transdermal patch, which usually relies on diffusion of the drug across the skin. However, the reliance on diffusion and skin barrier permeability (i.e., effective barrier properties) limits the substances, which may be administered by transdermal diffusion as a function of substance size, hydrophilicity and the concentration gradient across the barrier. Few compounds possess the necessary physiochemical properties to be effectively delivered through the skin by the passive diffusion of a transdermal patch.
Active diffusion techniques (e.g., iontophoresis, electroporation, ultrasound, and heat) have been used in an attempt to improve the rate of delivery. However, these techniques may be not suitable for all types of drugs, failing to provide the desired level of delivery efficiency. Additionally, these techniques may also be impractical, inconvenient and/or painful.
For example, U.S. Pat. No. 6,565,532 to Yuzhakov, et al., discloses a “Microneedle apparatus for marking skin and for dispensing semi-permanent subcutaneous makeup.” The microneedles disclosed can apply identifications or other tattoo-like graphics, and will not enter into the dermal layer of the skin so that the application procedure is painless. The microneedle array is also useful for delivering specific compounds or actives into the skin, such as cosmetic compounds or nutrients, or various skin structure modifiers that can be delivered subcutaneously without having to visit a cosmetic surgery clinic. The invention disclosed in the patent provides a method for manufacturing an array of microneedles using standard semiconductor fabrication techniques like silicon etching by which a silicon substrate was etched to create hollow or solid individual microneedles. Other micromolding methods including LIGA and deep LIGA processes and hot embossing and microinjection methods were used to fabricate polymeric microneedle arrays.
In another example, U.S. Pat. No. 6,503,231 to Prausnitz, et al., discloses a “Microneedle device for transport of molecules across tissue” and U.S. Pat. No. 6,334,856 to Allen, et al., discloses a “Microneedle device and methods of manufacture and use thereof.” The patents relate to methods for manufacturing an array of microneedles, which may be hollow and/or porous and have diameters between about 10 nm and 1 mm, fabricated by microfabrication techniques from metals, silicon, silicon oxide, ceramic, and polymeric materials. A reactive ion etch process is used to etch silicon with gas mixtures of SF6 and O2 to make tapered and sharp Si master mold, and then SiO2 or metal was deposited to form hollow microneedles. Finally, the hollow microneedle arrays were released from the silicon substrate by wet etching or dry etching. Further similar vertical hollow microneedles were created by resist patterning combined with underetching. With Si spikes, SU-8 resist casting method was used to make SU-8 mold and electroplating metals onto the SU-8 mold and removal of the SU-8 mold generated the tapered hollow metallic microneedles.
U.S. Pat. No. 6,511,463 Wood, et al., discloses methods of fabricating microneedle arrays using sacrificial molds and relates to methods of fabricating hollow vertical microneedle or tube arrays by use of multiple steps of molding with a master mold and a sacrificial mold. The patent discloses a microneedle array fabricated by providing a sacrificial mold including a substrate and an array of posts, preferably solid posts, projecting therefrom. A first material is coated on the sacrificial mold including on the substrate and on the array of posts. The sacrificial mold is removed to provide an array of hollow tubes projecting from a base.
What is need is a cost effective method of fabricating a delivery mechanisms that is relatively painless and facilitates transport of a variety of therapeutic or biologically active molecules across tissue barriers, such as for drug delivery or sampling of biological fluids.